Abstract
Twist-related protein 1 (Twist1), also known as class A basic helix-loop-helix protein 38 (bHLHa38), has been implicated in cell lineage determination and differentiation. Previous studies demonstrate that Twist1 expression is up-regulated in gastric cancer with poor clinical outcomes. Besides, Twist1 is suggested to be involved in progression of human gastric cancer. However, its biological functions remain largely unexplored. In the present study, we show that Twist 1 overexpression leads to a significant up-regulation of FoxM1, which plays a key role in cell cycle progression in gastric cancer cells. In contrast, knockdown of Twist 1 reduces FoxM1 expression, suggesting that FoxM1 might be a direct transcriptional target of Twist 1. At the molecular level, we further reveal that Twist 1 could bind to the promoter region of FoxM1, and subsequently recruit p300 to induce FoxM1 mRNA transcription. Therefore, our results uncover a previous unknown Twist 1/FoxM1 regulatory pathway, which may help to understand the mechanisms of gastric cancer proliferation.
Highlights
Epithelial-mesenchymal-transition (EMT) is a process whereby epithelial cells lose polarity and cell-to-cell adhesion, and undergo dramatic remodeling of the cytoskeleton [1,2]
Our results suggest that neither empty vector or green fluorescent protein (GFP) small interfering RNA (siRNA) affect the cell proliferation activity (Figure S2A)
Our results suggest that Twist 1 might be an important positive regulation of gastric cancer cell proliferation
Summary
Epithelial-mesenchymal-transition (EMT) is a process whereby epithelial cells lose polarity and cell-to-cell adhesion, and undergo dramatic remodeling of the cytoskeleton [1,2]. Concurrent with loss of epithelial cell adhesion and cytoskeletal components, cells undergoing EMT acquire expression of mesenchymal components and a migratory phenotype [2,3]. Several key inducers of EMT are transcription factors including Twist 1, Snail, and Slug, which repress E-cadherin expression [4,5]. Twist was suggested to be essential in the development of mesodermally derived tissues, including muscle and osteogenic cell lineages [7,8]. Subsequent studies have shown that Twist 1 promotes EMT and plays an essential role in metastasis in several tumor models [9,10]. Expression of Twist 1 has been implicated in promotion of metastasis and invasive pathological subtypes in several types of carcinoma [11].
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